title: Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation.
abstract: NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg(-1)·day(-1)) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Yushima, Bunkyo, Tokyo, Japan;
authors.forename: Ryo
authors.initials: R
authors.lastname: Watanabe
authors.forename: Ryoko Wakizono
authors.initials: RW
authors.lastname: Azuma
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogawa
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D001549:Benzamides; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
keywords: NF-κB kinase; inflammation; myocarditis